Summary: Protein Surface Mimicry by Peptidic Foldamers Foldamers are unnatural oligomers that display discrete and predictable folding behavior. The proposed research explores the ability of foldamers to mimic recognition surfaces on natural proteins and thereby block the formation of specific protein-protein complexes. Interactions between specific pairs of proteins are critical for regulation and information transfer in living systems. Pathological interactions contribute to many human diseases. Such interactions are often difficult to inhibit with small molecules (the traditionally preferred source for drugs) because large surface areas are buried when one macromolecule binds to another. A principal hypothesis behind our work is that foldamers could provide a basis for rational development of inhibitors of protein-protein interactions. We are testing this hypothesis in three systems. First, we are trying to mimic alpha-helical Bcl-2 homology-3 (BH3) domains, segments of natural pro-apoptotic proteins that are recognized by complementary clefts on anti- apoptotic partner proteins. This system represents an excellent testbed for our efforts because robust protein-based assays are available, and there is a good prospect of acquiring thermodynamic data and high-resolution structural data. Strategies that are successful for BH3 domain mimicry will be examined in the context of a longer alpha-helical target, the C-terminal heptad repeat (CHR) segment of the HIV protein gp41. The CHR helix must dock into a complementary cleft formed by another portion of gp41 in order for the virus to infect target cells. Blocking this interaction can block infection. The final test of our hypothesis focuses on inhibiting interactions between vascular endothelial growth factor (VEGF), a soluble signaling protein, and its cell-surface receptors. VEGF induces development of new blood vessels (angiogenesis), and aberrant VEGF-induced angiogenesis is associated with a number of human diseases. Strategies identified in this component of our research could ultimately enable us to develop foldamer antagonists for a wide range of protein-receptor interactions that occur at the cell surface.